Tuesday, May 5, 2015

Unprecedented international coalition
led to breakthrough for patients with deadliest form of childhood brain cancer,
as released today in Nature Medicine.

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[press release] FORT COLLINS, CO,
May 4, 2015 – Researchers from an international coalition of 13 institutions
have discovered a promising combination drug therapy for the deadly childhood
cancer Diffuse Intrinsic Pontine Glioma (DIPG). In a study published
today in Nature Medicine co-authored by Michelle Monje,
MD, PhD (Stanford University) and Charles Keller, MD (Children’s Cancer Therapy
Development Institute), the consortium reports that testing of panobinostat,
with or without the histone demethylase inhibitor GSKJ4, may be a promising
therapeutic strategy for this deadly pediatric brain tumor.

DIPG is a rare tumor of the brainstem
that occurs almost exclusively in children under 10 years old. It represents
one of the most devastating diagnoses among pediatric cancers, with an average
survival rate of just nine months. As co-Chairs of the Children’s Oncology
Group brain tumor new drugs committee, Dr. Keller and Dr. Maryam Fouladi built
and coordinated the group of basic and translational scientists who formed the
unprecedented coalition. The project was sponsored by the Lyla Nsouli
Foundation, The CureStartsNow, Curesearch and Accelerate Brain Cancer Cures and
supported by multiple gifts of tumor tissue from children who did not survive.

“The story of how the consortium
started is a fun one,” explained Keller. “In a packed St Louis hotel meeting
room a few years ago, our committee put forth ideas for the next DIPG clinical
trial. It became clear that the nation’s best oncologists had lots of ideas,
but we all had no data…so we decided to have a “bake-off”. Maryam rallied the
pediatric neuro-oncologists, and I coordinated and recruited the research
teams. Eighty-three drugs later, we have an answer.”

The work began with a chemical screen
in patient-derived DIPG cultures along with RNAseq analyses and integrated
computational modeling to identify potentially effective therapeutic
strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated
efficacy in vitro and in DIPG orthotopic xenograft (mouse) models. Further
testing of panobinostat with histone demethylase inhibitor GSKJ4 revealed
synergy in combination. A clinical trial is currently being designed for
single-drug therapy with panobinostat, which will likely begin enrolling
patients later this year.

“This panobinostat clinical trial is
really the first step,” Keller said. “We can be fairly certain that as the
‘world’s most difficult cancer to treat,’ DIPG will take more than one drug to
cure. As promising as the panobinostat-GSKJ4 combination is, we may need to go
further—even exploring non-traditional compounds not yet used as medicines.”

“The manuscript by Grasso, Tang,
Truffaux et al is an outstanding example of cooperation among dedicated
laboratory based scientists and clinicians who have pooled resources and freely
shared data to impact the treatment of a rare but fatal brain tumor in
children. A special recognition should be given to community-based
organizations that provided philanthropic support to enable the study. This
model of translational research should be encouraged and fostered to improve
outcome for rare human disease,” said Amar Gajjar, MD, Chair of the Central
Nervous System Tumor Committee, Children's Oncology Group and neuro-oncologist
at St. Jude Children’s Research Hospital.

“In a disease where no therapeutic
progress has been made in several decades, we see the culmination of
the efforts of an international group of basic and translational
investigators who have collaborated together to better
understand potential therapeutic targets and conduct preclinical testing
of promising agents targeting relevant pathways in this deadly disease.
The fact that Drs. Monje & Keller and colleagues demonstrated that the
combination of panobinostat and the GSKJ4 demonstrate synergy is very
promising. The Children’s Oncology Group was the catalyst for fostering these
efforts over the past three years, with funding coming from philanthropic
agencies who also banded together to support these efforts. The next step
is to develop clinical trials to assess the efficacy of these agents alone
and in combination in patients with DIPG. Based on data presented in this
paper, the Pediatric Brain Tumor Consortium is moving forward with a new study
to test panobinostat in children with newly diagnosed and recurrent
DIPGs. I hope that the results generated from these
critical preclinical collaborations will lead to the development of novel
combination trial strategies to effectively treat children with this
deadly tumor,” said Maryam Fouladi, MD, Chair of the Pediatric Brain Tumor
Consortium Steering Committee and Medical Director of the Neuro-Oncology
Program at Cincinnati Children’s Hospital Medical Center.

​

"For as long as DIPG has been
specifically classified, parents of children diagnosed with this cancer have
longed for effective treatments. This represents an exciting and promising
new chapter that finally provides hope. Since the time of my daughter Alexis'
diagnosis in April 2008, and her passing in January 2011, little has
changed…until now. I am beyond hopeful that this now represents that
change,” said Jonathan Agin, childhood cancer advocate and cc-TDI General
Counsel. Agin lost his daughter Alexis to DIPG when she was two weeks away from
her fifth birthday.

​

"We are very enthusiastic about
the work of Dr. Keller, Dr. Monje and the DIPG consortium and are excited by
the study findings about panobinostat. This drug offers a new path of study
with the potential to create treatment options for DIPG. We look forward to the
next steps of research and are hopeful that this progress brings us closer to
helping children with DIPG to survive.”

Based in Fort Collins, Colorado, the
Children's Cancer Therapy Development Institute is a unique research group that
is focused on closing what is known as the "pre-clinical gap" in
childhood cancer research. To end the stalemate in curing childhood cancers,
cc-TDI is dedicated to translating knowledge from basic scientific advancements
into proven, viable treatment options that can be tested in clinical trials,”
comments Nadim Nsouli on behalf of the Lyla Nsouli Foundation, the principal
sponsor of the international research effort. Mr. Nsouli, and his wife Simone,
founded the Lyla Nsouli Foundation after the passing of their 4 year old
daughter, Lyla, as a result of DIPG. Her mother adds, “We miss Lyla
terribly. She was truly our pride and joy.”

​

Sandy Smith, an advocate for childhood
cancer and a cancer survivor herself offered this perspective: “I was diagnosed
with breast cancer on Monday, October 22, 2007. My 6-year-old son Andrew was
diagnosed with diffuse intrinsic pontine glioma (DIPG) just a few days later.
We both ended up with ports, we both did chemotherapy and radiation, and we
both lost our hair; but that’s where the similarities end. My treatment was
standard and my prognosis favorable. There was no hope of a cure for Andrew;
radiation was palliative. While we pushed through my treatment, my husband and
I did our best to savor every moment with our son because we knew those moments
were very limited. This publication—the result of selfless collaboration by
dedicated scientists from around the world—is a step toward progress for
children with DIPG. This is meaningful science making a difference in the lives
of children and families like mine.”

“This is a journey and a partnership
with families. One of the most interesting features of the project is
that we kept a weekly blog of research activities - which
allowed families to follow progress with us (and give feedback). We still need
more tissue, better cell lines, and more mouse models. Our 15 institutions
are unified by the community support that brought us together and keeps us
focused. We’ll continue pursuing better and better treatments until the day
that DIPG is uniformly survivable,” Keller added.

For more on cc-TDI’s efforts to move
scientific discoveries to clinical trials for children with cancers like DIPG,
visit www.cc-TDI.org.

The Children's Cancer Therapy
Development Institute was created with one aim: to make childhood cancer
universally survivable, regardless of diagnosis. Our mission is to
translate scientific discovery into clinical trials by understanding and
proving new disease-specific treatment options for children with cancer. Our
team, led by Scientific Director Charles Keller, MD, is discovering and proving
new disease-specific treatments in our Innosphere lab at the base of the Rocky
Mountains.

our team

click below to

about us

Click Below for KellerLab Papers on Pubmed:

a community resource for families

You Can Participate in our Novel Therapeutics Studies !

One would like to think that tangibly better treatments for rhabdomyosarcoma, medulloblastoma and other childhood cancers can be found in a matter of years, instead of tens of years. Finding new treatments starts with research, perhaps even a new research approach to identifying effective new treatments. The Children's Cancer Therapy Development Institutefocuses on finding molecules in childhood cancers that can be directly turned off or on by drugs so that the tumor stops growing. Behind our novel approach is the use of genetically-engineered mice. Our Pediatric Preclinical Testing Initiative uses mice modified from before birth so that at a certain age, and in a certain tissue, the same mutations found in a child’s cancer are activated in the mouse. These special mouse models of childhood cancer can be used to test a treatment to see whether the tumor growth and spread (metastasis) can be reversed. The specific aspect of these mice having normal immune systems is a real plus, too, because white blood cells play an important role in how tumors evolve and respond to therapy.

Our program is designed around community participation. Through the Children's Cancer Therapy Development Institute, you can contribute directly to this grass-roots initiative. Donations through small gifts or grants will assist in studying compounds that may be effective in treating such childhood cancers as alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma, or medulloblastoma (the alveolar rhabdomyosarcoma model was featured by Dr. Keller's long time collaborator and former mentor, 2007 Nobel laureate Mario Capecchi, in his Nobel Prize lecture {see 16 minutes onward}.)

For additional information regarding supporting this program please contact Charles Keller at charles@cc-tdi.org. Results obtained through these studies will be shared with the National Cancer Institute’s Cancer Therapy Evaluation Program, as well as the Children’s Oncology Group, which designs clinical trials for childhood cancer.